Understanding sex differences in the initiation to addiction are important goals as evidenced by the FOA (PAS-07-382) to which this exploratory grant is addressed. We propose a novel yet hypothesis-based approach to examine sex differences in stress responsivity and addiction using established animal procedures. Stress responsivity relates to acquisition of cocaine self-administration, an animal model of vulnerability to addiction. Stress responsivity shows sex differences but reports on self-administration are conflicting. Links between maternal care and stress responsivity of offspring are proposed; greater care relates to lower stress responsivity of adults. Maternal care differs by pup sex; male pups receive more care than female pups. Adult males show lower stress responsivity than females consistent with the link of maternal care with stress responsivity. We hypothesize that sex-dependent maternal care influences sex differences in stress responsivity and cocaine self-administration in the adult. We will test this by manipulating maternal care via altering litter gender composition (LGC; single- vs mixed-sex litters) because pups of single-sex litters receive more care than pups of mixed-sex litters. LGC influences stress responsivity in infant mice and juvenile and maternal behaviors in rats and mice. We predict both male and female adult rats of single-sex litters will show lower stress responsivity than offspring of mixed-sex litters. In Specific Aim 1, we will confirm prior studies demonstrating sex-specific effects of maternal care. We will measure stress hormone levels after stress exposures and assess glucocorticoid feedback sensitivity. We predict the following effects of LGC on stress responsivity: mixed females>single females >=mixed males>single males. The relationship between stress responsivity and cocaine self-administration is complex and may be non-linear; both low and high stress responsivity may associate with low responding. Thus, we predict LGC will attenuate acquisition of cocaine self-administration in mixed females and single males and, overall, result in an inverted U-shaped function of stress responsivity to cocaine self-administration. Studies in Specific Aim 2 will test the effects of LGC on acquisition of cocaine self-administration with a parallel study on acquisition of food responding. Behavioral sensitivity to foot shock will also be investigated. Data will inform on contributions of stress responsivity to sex differences in vulnerability to addiction. PUBLIC HEALTH RELEVANCE: The goal of this research program is to achieve a better understanding of sex differences in stress responsivity and vulnerability to addiction using animal models. Studies in this proposal will test the hypothesis that these sex differences are due to sex-dependent differences in maternal care received suggestive of epigenetic origins of the sex differences in stress and drug responses in the adult. [unreadable] [unreadable] [unreadable]